The purpose of the proposed K01 Mentored Research Scientist Development Award is to provide the candidate with research training experiences needed to support her career goal of becoming an alcohol investigator who aims to understand the interplay between genetic factors and close relationship factors in the onset, persistence, and discontinuity of alcohol misuse (i.e., risky drinking and alcohol use disorder). To expand her research career and support this career goal, the candidate's training goals under this award are to: (1) establish an integrated understanding of alcohol misuse in emerging adulthood that formally ties together her research interests in alcohol outcomes, romantic relationships, and behavior genetics; and (2) develop a solid foundation in the use and interpretation of advanced genetic (e.g., next generation sequencing), genomic (e.g., functional annotation), and statistical (e.g., structural equation modeling) methods needed to carry out an independent interdisciplinary program of research on gene-environment interplay in the development of alcohol misuse. These goals will be achieved through a structured series of mentored research experiences, a molecular genetics laboratory rotation, coursework/workshops in bioinformatics and statistical genetics, directed readings with mentors and collaborators who are experts in their respective fields, and exposure to clinical interventions for hazardous/harmful drinking. The candidate will also participate in additional activities to further support her career development including training in the responsible conduct of research, grant writing, and presenting research at professional conferences. The candidate will complete this training at Virginia Commonwealth University (VCU) under the primary mentorship of Dr. Danielle Dick (expertise in gene-environment interplay for alcohol use disorder), with co-mentorship provided by Dr. Thomas Dishion (expertise in pathways toward adolescent and adult substance use, with an emphasis on interpersonal factors), Dr. Mikhail Dozmorov (expertise in bioinformatics and biostatistics), and Dr. Shaunna Clark (expertise in structural equation modeling). Alcohol and behavior genetics are active areas of research at VCU, and thus the candidate has unparalleled support and resources to further her research career. The scientific objective of this proposal is to examine how alcohol dependence genetic predispositions influence pathways to emerging adulthood (ages 18-29) relationship quality and partner selection, and how characteristics of one's relationship and partner further shape trajectories of alcohol misuse. The central hypothesis is that gene-environment correlation (rGE) and gene-environment interaction (G x E) processes contribute to these pathways and trajectories. The candidate's approach leverages novel training in bioinformatics to characterize aggregate genetic risk for alcohol dependence by creating biologically refined polygenic scores. The candidate will then use biologically refined polygenic scores to test gene-environment interplay hypotheses in two NIAAA-funded genetically informative prospective longitudinal studies of emerging adults: Spit for Science (PIs: Dick and Kendler) and the Project Alliance 1 (PAL-1) Relationship Study (PI: Dishion). Spit for Science is a sample of four cohorts of college freshmen (n~10,000) who are followed annually (ages ~18-23). The PAL-1 Relationship Study is a sample of ~400 romantic dyads (ages ~28-29). One partner in each dyad has been studied since adolescence, and a videotaped couple's assessment and dyadic longitudinal phenotypic data are collected as part of the relationship study. These studies complement one another in that Spit for Science allows the candidate to examine how the hypothesized gene-environment interplay effects unfold across a six-year period covering the beginning of emerging adulthood, and PAL-1 will provide insights into how the hypothesized effects play out in a specific dyadic relationship in the latter part of emerging adulthood. The three aims of this work are to: (1) Examine whether alcohol dependence genetic predispositions are associated with the quality of one's relationship or the alcohol misuse of one's romantic partner (i.e., rGE), and whether these associations are mediated by antisocial behavior and affiliations with deviant peers in adolescence; (2) Examine whether the quality of one's relationship or the alcohol misuse of one's romantic partner moderate alcohol dependence genetic predispositions to predict alcohol misuse (i.e., G x E); (3) Examine whether the patterns observed in Aims 1 and 2 differ by sex. This research is significant because it fills a critical need for studies of gene-environment interplay for alcohol misuse and romantic relationship factors in emerging adulthood, which is the period of highest risk for the development of alcohol use disorder. Furthermore, the candidate's proposal to integrate alcohol dependence genome-wide association study results and functional annotation information to develop biologically refined polygenic scores is an innovative departure from the candidate gene approach typically adopted in studies of gene-environment interplay in alcohol research. In summary, the proposed award will provide the candidate with new research and training experiences needed to launch an independent, innovative research program on genetics, romantic relationships, and alcohol misuse that is relevant to NIAAA's mission to identify how genetic and salient environmental risk and protective factors for alcohol misuse interface across development.